The long-term objective of the proposed research is to develop a new therapeutic drug regimen that could be employed either alone or in combination for the treatment of acquired immunodeficiency syndrome (AIDS). To achieve this goal, a multidisciplinary effort will be initiated to design and synthesize a series of novel prodrugs of selected inhibitors of the enzyme reverse transcriptase of human immunodeficiency virus (HIV) to achieve higher intracellular drug concentrations and to overcome the blood brain barrier for attacking the sanctuary of HIV in the CNS. Initially, 2',3'-dideoxynucleosides (e.g. azidothymidine and dideoxycytidine) will be modified to obtain the following prodrugs: (a) esters containing various functionalities such as N-N- substituted amides, morpholine, N-methylpiperazine, and N- phenylpiperazine; (b) amino acid analogs to utilize the amino acid transport mechanism; (c) polyamine analogs to employ the rapid uptake mechanism of polyamines specifically in polyamine depleted cells; (d) dihydropyridine analogs to use a redox chemical drug-delivery system that would allow a sustained delivery of drugs to the brain. The physicochemical properties such as partition coefficients and protein binding capacities will be determined for correlative studies with antiviral activity. Evaluation of intracellular uptake and antiviral activity of prodrugs will be detemined in vitro by employing HIV infected in both monocytic (U937) and lymphoid (H9 or ATH8) cell lines. Active agents resulting from this program will be studied in mice and rabbits for pharmacokinetic parameters to determine the extent and rate of entry of various prodrugs in brain tissue and cerebrospinal fluid. The multidisciplinary approach of this application will allow maximum efficiency in the development of the most effective prodrug of antiretroviral agents that can be used for the treatment of AIDS.